Multiple sclerosis, a chronic immune-mediated disease of the central nervous system, is considered an autoimmune disease. Statins are safe cholesterol-lowering drugs and have immunomodulatory effects, ranging from reducing migration across the blood brain barrier to neuroprotective functions. To establish the immunological effects of 80mg daily of simvastatin, a randomised, placebo-controlled, double-blind clinical trial of 140 secondary progressive multiple sclerosis (SPMS) patients was set up, with screening visits at months 0, 6, 12 and 24. The effects of several parameters were investigated on peripheral blood mononuclear cells (PBMC), their function, the molecules involved in antigen presentation, lymphocyte regulation, and adhesion. Initially, the need for age-matched controls was demonstrated, due to age-dependent effects on various molecules associated with regulatory T cells, T cell proliferation, and CD49d expression on monocytes. Subsequently, PBMCs from SPMS patients compared with healthy controls showed decreases in CD4+CD25+, TGFβ and IL-10 expression, and the Th2 and Th17 T cell populations, while the regulatory CD4+FoxP3+ T cell population increased. Finally, 24 months of simvastatin treatment failed to demonstrate any major changes in the immune cells of SPMS patients, although the drug appeared to have a stabilizing effect on certain molecules. When comparing the simvastatin- to placebo-treated patients PBMCs these displayed increases in MAC-1 and HLA-DR expression on monocytes and CD40L and IL-4 expression on lymphocytes. Some of these changes were transient, whereas monocyte HLA-DR and T cell IL-4 expression increased at 24 months, suggesting simvastatin treatment can lead to long-term immunomodulatory changes. Additionally, an inhibitory effect of simvastatin in vitro was demonstrated on expression of CXCR3 and migration of mononuclear (THP-1) cells. Although statins induce significant effects in vitro, such effects were fewer with simvastatin therapy in SPMS patients.